! 7. Project Summary This K23 application will support my plan to build a research career in mechanism-oriented clinical research in asthma. Specifically, a K23 will provide me with the support necessary to accomplish the following goals: (i) to build a patient-centered research program focused on discovering the mechanistic underpinning of disease heterogeneity in asthma; (ii) to learn methods of translational clinical research, including design of clinical research studies with mentoring in epidemiology and biostatistical methods; (iii) to learn molecular methods, including immunoassays and gene transcription profiling; (iv) to advance my knowledge of immunology, cellular biology, and molecular biology to improve my ability to generate hypotheses for disease endotypes in asthma. To achieve these four goals, I have assembled a strong mentoring team and a rigorous and innovative research plan centered on metabolic dysfunction and aging as a mediators of severe asthma: Mentoring Team: John Fahy, M.D., (primary mentor) has expertise in mechanism-oriented research in asthma and in airway epithelial cell biology. Dr Fahy has previously been the primary mentor for four pulmonary fellows who have been awarded K grants. Prescott Woodruff, M.D., MPH is a clinical researcher in airway disease with particular expertise in asthma, clinical research and epidemiology, and in the analysis of complex data sets that arise in genomics-based studies of gene expression. Jeoung-Sook Shin, PhD. is an immunologist with expertise in dendritic cell biology and a disease focus on asthma. Her laboratory is experienced in how to apply multi-color flow cytometry to the analysis of immune cells in human biospecimens; Charles McCulloch, Ph.D. is an expert in biostatistics with a focus in the statistical methods for longitudinal analysis, mixed models, and latent class models. Suneil Koliwad. M.D., PhD. Is an endocrinologist who studies the role of obesity associated chronic inflammation in the development of type-2 diabetes and activation of innate immune cells. Research Plan: Developing successful treatments for severe asthma will require a more nuanced understanding of the molecular pathways that lead to severe disease. Increased airway type-2 inflammation is a well-established pathway in asthma, but very little is known regarding the other non-type pathways that drive severe asthma. Studies that have systematically examined disease heterogeneity in asthma find that older age and high body weight are features of more severe asthma, and these features provide clues about disease mechanisms. For example, I recently found that systemic IL6 inflammation occurs in a subset of asthmatics characterized by older age, obesity, metabolic dysfunction, and severe asthma. In this K23 application I will further explore the clinical, metabolic, and inflammatory features of severe asthma in the NHLBI Severe Asthma Research Program (SARP) with an emphasis on longitudinal analyses and a focus on IL6- and obesity-related inflammation (Aims 1 and 2) and on age-related changes in airway type 2 inflammation (Aim 3). !